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Alimentary Pharmacology & Therapeutics Jan 2020The pathogenesis of infant colic is poorly defined. Gut microbiota seems to be involved, supporting the potential therapeutic role of probiotics. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The pathogenesis of infant colic is poorly defined. Gut microbiota seems to be involved, supporting the potential therapeutic role of probiotics.
AIMS
To assess the rate of infants with a reduction of ≥50% of mean daily crying duration after 28 days of intervention with the probiotic Bifidobacterium animalis subsp. lactis BB-12 (BB-12). Secondary outcomes were daily number of crying episodes, sleeping time, number of bowel movements and stool consistency.
METHODS
Randomized controlled trial (RCT) on otherwise healthy exclusively breastfed infants with infant colic randomly allocated to receive BB-12 (1 × 10 CFU/day) or placebo for 28 days. Gut microbiota structure and butyrate, beta-defensin-2 (HBD-2), cathelicidin (LL-37), secretory IgA (sIgA) and faecal calprotectin levels were assessed.
RESULTS
Eighty infants were randomised, 40/group. The rate of infants with reduction of ≥50% of mean daily crying duration was higher in infants treated with BB-12, starting from the end of 2nd week. No infant relapsed when treatment was stopped. The mean number of crying episodes decreased in both groups, but with a higher effect in BB-12 group (-4.7 ± 3.4 vs -2.3 ± 2.2, P < 0.05). Mean daily stool frequency decreased in both groups but the effect was significantly higher in the BB-12 group; stool consistency was similar between the two groups. An increase in Bifidobacterium abundance (with significant correlation with crying time reduction), butyrate and HBD-2, LL-37, sIgA levels associated with a decrease in faecal calprotectin level were observed in the BB-12 group.
CONCLUSIONS
Supplementation with BB-12 is effective in managing infant colic. The effect could derive from immune and non-immune mechanisms associated with a modulation of gut microbiota structure and function.
Topics: Bifidobacterium animalis; Breast Feeding; Colic; Crying; Defecation; Double-Blind Method; Feces; Female; Gastrointestinal Microbiome; Humans; Infant; Infant Care; Male; Placebos; Probiotics; Treatment Outcome
PubMed: 31797399
DOI: 10.1111/apt.15561 -
Supportive Care in Cancer : Official... Nov 2020Transcutaneous electrical nerve stimulation (TENS) is a treatment option for cancer pain, but the evidence is inconclusive. We aimed to evaluate the efficacy and safety... (Randomized Controlled Trial)
Randomized Controlled Trial
Transcutaneous electrical nerve stimulation for advanced cancer pain inpatients in specialist palliative care-a blinded, randomized, sham-controlled pilot cross-over trial.
PURPOSE
Transcutaneous electrical nerve stimulation (TENS) is a treatment option for cancer pain, but the evidence is inconclusive. We aimed to evaluate the efficacy and safety of TENS.
METHODS
A blinded, randomized, sham-controlled pilot cross-over trial (NCT02655289) was conducted on an inpatient specialist palliative care ward. We included adult inpatients with cancer pain ≥ 3 on an 11-point numerical rating scale (NRS). Intensity-modulated high TENS (IMT) was compared with placebo TENS (PBT). Patients used both modes according to their preferred application scheme during 24 h with a 24-h washout phase. The primary outcome was change in average pain intensity on the NRS during the preceding 24 h. Responders were patients with at least a "slight improvement."
RESULTS
Of 632 patients screened, 25 were randomized (sequence IMT-PBT = 13 and PBT-IMT = 12). Finally, 11 patients in IMT-PBT and 9 in PBT-IMT completed the study (N = 20). The primary outcome did not differ between groups (IMT minus PBT: - 0.2, 95% confidence interval - 0.9 to 0.6). However, responder rates were higher in IMT (17/20 [85%] vs. 10/20 [50%], p = 0.0428). Two patients experienced an uncomfortable feeling caused by the current, one after IMT and one after PBT. Seven patients (35%) desired a TENS prescription. Women and patients with incident pain were most likely to benefit from TENS.
CONCLUSION
TENS was safe, but IMT was unlikely to offer more analgesic effects than PBT. Even though many patients desired a TENS prescription, 50% still reported at least "slight pain relief" from PBT. Differences for gender and incident pain aspects demand future trials.
Topics: Adult; Aged; Cancer Pain; Cross-Over Studies; Disease Progression; Female; Germany; Humans; Inpatients; Male; Middle Aged; Neoplasms; Pain Management; Pain Measurement; Palliative Care; Pilot Projects; Placebos; Transcutaneous Electric Nerve Stimulation; Treatment Outcome
PubMed: 32128614
DOI: 10.1007/s00520-020-05370-8 -
PLoS Medicine Sep 2020Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their...
BACKGROUND
Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions.
METHODS AND FINDINGS
We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator.
CONCLUSIONS
We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.
Topics: Checklist; Humans; Placebos; Research Design; Research Personnel; Research Report; Surveys and Questionnaires
PubMed: 32956344
DOI: 10.1371/journal.pmed.1003294 -
Archivum Immunologiae Et Therapiae... Mar 2021
Topics: Humans; Antiviral Agents; Controlled Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; Evidence-Based Medicine; Placebos; United States; United States Food and Drug Administration
PubMed: 33782781
DOI: 10.1007/s00005-021-00612-x -
British Journal of Anaesthesia Aug 2019Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in... (Review)
Review
Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in pharmacological trials and marked placebo effects are found in neurostimulation and surgical trials, thereby posing the question whether non-pharmacological interventions should be placebo-controlled to a greater extent. In this narrative review we discuss how the knowledge of placebo mechanisms may help to improve placebo control in pharmacological and non-pharmacological trials. We review the psychological, neurobiological, and genetic mechanisms underlying placebo analgesia and outline the current problems and potential solutions to the challenges with placebo control in trials on pharmacological, neurostimulation, and surgical interventions. We particularly focus on how patients' perception of the therapeutic intervention, and their expectations towards treatment efficacy may help develop more precise placebo controls and blinding procedures and account for the contribution of placebo factors to the efficacy of active treatments. Finally, we discuss how systematic investigations into placebo mechanisms across various pain conditions and types of treatment are needed in order to 'personalise' the placebo control to the specific pathophysiology and interventions, which may ultimately lead to identification of more effective treatment for pain patients. In conclusion this review shows that it is important to understand how patients' perception and expectations influence the efficacy of active and placebo treatments in order to improve the test of new treatments. Importantly, this applies not only to assessment of drug efficacy but also to non-pharmacological trials on surgeries and stimulation procedures.
Topics: Analgesia; Humans; Pain; Placebo Effect; Placebos; Treatment Outcome
PubMed: 30915982
DOI: 10.1016/j.bja.2019.01.040 -
PLoS Medicine Nov 2021Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear.
METHODS AND FINDINGS
We conducted a systematic review and meta-analysis to evaluate the extent to which specific drug groups are associated with OH. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Placebo-controlled randomised controlled trials (RCTs) on any drug reporting on OH as an adverse effect in adults (≥18 years) were eligible. Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to appraise evidence. Summary odds ratios (ORs) were estimated for OH using fixed effects Mantel-Haenszel statistics. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. There was no statistically significant difference in odds of OH with vasodilators (CCBs, ACE inhibitors/ARBs, SSRIs), compared to placebo. Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. The study protocol is publicly available on PROSPERO (CRD42020168697).
CONCLUSIONS
Medications prescribed for common conditions (including depression, diabetes, and lower urinary tract symptoms) were associated with significantly increased odds of OH. Drugs causing sympathetic inhibition were associated with significantly increased odds of OH, while most vasodilators were associated with small nonsignificant differences in odds of OH, compared to placebo. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. sympathetic inhibition, vasodilation, cardio-inhibitory effects) may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from postural BP monitoring.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antidepressive Agents; Antipsychotic Agents; Humans; Hypotension, Orthostatic; Placebos; Randomized Controlled Trials as Topic; Vasodilator Agents
PubMed: 34752479
DOI: 10.1371/journal.pmed.1003821 -
Lancet (London, England) Mar 2020Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a... (Review)
Review
Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial.
Topics: Guidelines as Topic; Humans; Placebos; Randomized Controlled Trials as Topic; Research Design; Surgical Procedures, Operative
PubMed: 32145797
DOI: 10.1016/S0140-6736(19)33137-X -
Psychological Medicine Oct 2020Placebos are not inert, but exert measurable biological effects. The placebo response in psychiatric illness is important and clinically relevant, but remains poorly... (Review)
Review
Placebos are not inert, but exert measurable biological effects. The placebo response in psychiatric illness is important and clinically relevant, but remains poorly understood. In this paper, we review current knowledge about the placebo response in psychiatric medicine and identify research directions for the future. We argue that more research is needed into the placebo response in psychiatric medicine for three broad reasons. First, awareness of factors that cause placebo response, for whom, and when, within clinical trials will allow us to better evidence efficacy of new treatments. Second, by understanding how placebo mechanisms operate in the clinic, we can take advantage of these to optimise the effects of current treatments. Finally, exploring the biological mechanisms of placebo effects might reveal tractable targets for novel treatment development.
Topics: Clinical Trials as Topic; Humans; Mental Disorders; Placebo Effect; Placebos; Psychiatry
PubMed: 33028433
DOI: 10.1017/S0033291720003633 -
The Cochrane Database of Systematic... Nov 2020Stroke is the second leading cause of death and a major cause of morbidity worldwide. Retrospective clinical and animal studies have demonstrated neuroprotective...
BACKGROUND
Stroke is the second leading cause of death and a major cause of morbidity worldwide. Retrospective clinical and animal studies have demonstrated neuroprotective effects of iron chelators in people with haemorrhagic or ischaemic stroke. This is the first update of the original Cochrane Review published in 2012.
OBJECTIVES
To evaluate the effectiveness and safety of iron-chelating drugs in people with acute stroke.
SEARCH METHODS
We searched the Cochrane Stroke Group Trials Register (2 September 2019), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2019, Issue 9; 2 September 2019), MEDLINE Ovid (2 September 2019), Embase Ovid (2 September 2019), and Science Citation Index (2 September 2019). We also searched ongoing trials registers.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of iron chelators versus no iron chelators or placebo for the treatment of acute stroke, including subarachnoid haemorrhage.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the search results. We obtained the full texts of potentially relevant studies and evaluated them for eligibility. We assessed risk of bias using the Cochrane 'Risk of bias' tool, and the certainty of evidence using the GRADE approach.
MAIN RESULTS
Two RCTs (333 participants) were eligible for inclusion; both compared the iron-chelating agent deferoxamine against placebo. Both studies evaluated participants with spontaneous intracerebral haemorrhage. We assessed one study to have a low risk of bias; the other study had potential sources of bias. The limited and heterogeneous data did not allow for meta-analysis of the outcome parameters. The evidence suggests that administration of deferoxamine may result in little to no difference in deaths (8% in placebo vs 8% in deferoxamine at 180 days; 1 RCT, 291 participants; low-certainty evidence). These RCTs suggest that there may be little to no difference in good functional outcome (modified Rankin Scale score 0 to 2) between groups at 30, 90 and 180 days (placebo vs deferoxamine: 67% vs 57% at 30 days and 36% vs 45% at 180 days; 2 RCTs, 333 participants; low-certainty evidence). One RCT suggests that administration of deferoxamine may not increase the number of serious adverse events or deaths (placebo vs deferoxamine: 33% vs 27% at 180 days; risk ratio 0.81, 95 % confidence interval 0.57 to 1.16; 1 RCT, 291 participants; low-certainty evidence). No data were available on any deaths within the treatment period. Deferoxamine may result in little to no difference in the evolution of National Institute of Health Stroke Scale scores from baseline to 90 days (placebo vs deferoxamine: 13 to 4 vs 13 to 3; P = 0.37; 2 RCTs, 333 participants; low-certainty evidence). Deferoxamine may slightly reduce relative oedema surrounding intracerebral haemorrhage at 15 days (placebo vs deferoxamine: 1.91 vs 10.26; P = 0.042; 2 RCTs, 333 participants; low-certainty evidence). Neither study reported quality of life.
AUTHORS' CONCLUSIONS
We identified two eligible RCTs for assessment. We could not demonstrate any benefit for the use of iron chelators in spontaneous intracerebral haemorrhage. The added value of iron-chelating therapy in people with ischaemic stroke or subarachnoid haemorrhage remains unknown.
Topics: Acute Disease; Bias; Deferoxamine; Hemorrhagic Stroke; Humans; Iron Chelating Agents; Neuroprotective Agents; Placebos; Randomized Controlled Trials as Topic
PubMed: 33236783
DOI: 10.1002/14651858.CD009280.pub3 -
The Cochrane Database of Systematic... Jan 2021Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap. However, the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria. This is an update of previously published versions of this review.
OBJECTIVES
To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references. Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 07 December 2020.
SELECTION CRITERIA
All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed the trial eligibility, methodological quality and extracted the data.
MAIN RESULTS
Six trials were found, of which three trials reporting the results of a total of 56 participants, were suitable for inclusion in the review. The blood tyrosine concentrations were significantly higher in the participants receiving tyrosine supplements than those in the placebo group, mean difference 23.46 (95% confidence interval 12.87 to 34.05). No significant differences were found between any of the other outcomes measured. The trials were assessed as having a low to moderate risk of bias across several domains.
AUTHORS' CONCLUSIONS
From the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced into routine clinical practice. Further randomised controlled studies are required to provide more evidence. However, given this is not an active area of research, we have no plans to update this review in the future.
Topics: Dietary Supplements; Humans; Intelligence; Neuropsychological Tests; Phenylalanine; Phenylketonurias; Placebos; Randomized Controlled Trials as Topic; Tyrosine
PubMed: 33427303
DOI: 10.1002/14651858.CD001507.pub4